Approximately 70% of patients with cancer experience pain attributable to their neoplasm or its therapy. As life expectancy has increased in developed and developing countries, cancer and cancer-related pain have become major social and medical concerns. The worldwide availability of opioid analgesics, the primary therapy for most cancer-related pain, varies greatly. In 1991, 20 developed countries accounted for 86% of the morphine consumed in the world while the remaining 14% of morphine was consumed in the remaining countries having the majority of the world's population. (Joranson, D. E., Journal of Pain and Symptom Management, 8(6):353-360, 1993).
The scant use of opiates for the relief of cancer pain for the majority of the world's population is a result of many factors including concerns over drug diversion for illicit use and addiction. Further, many patients with cancer-related pain require long-term continuous dosing of opioid analgesics which often necessitates the ingestion of multiple pills or tablets many times a day. Compliance with this dosing scheme is often poor. Further, enteral drug delivery is poorly tolerated or prohibited in many patients with cancer-related pain in whom continuous drug delivery is a necessity. However, continuous parenteral delivery of opioid analgesics is expensive, cumbersome, and dependent upon the availability of refrigeration, catheters, pumps and trained personnel.
Drug addiction is a major societal problem throughout the world. In the United States alone, on any given day, there are several hundred thousand addicts who are enrolled in treatment clinics. Most of them are placed on "methadone maintenance" as a basic part of their therapy. Major behavioral and compliance problems commonly complicate treatment.
The cost of "methadone maintenance" therapy is several hundred dollars per month per patient. A significant portion of this cost relates to the frequent clinic visits and the monitoring of urine tests that are run to assure proper compliance with drug dosing, as well as the pharmacy charges relating to methadone dispensing.
Delivery systems and devices for controlled release of drugs; i.e., controlled release and sustained or prolonged release, are well known in the art. A variety of methods have been described in the literature, including the physiological modification of absorption or excretion, modification of the solvent, chemical modification of the drug, absorption of drug on an insoluble carrier, use of suspensions and implantation pellets. Other methods include mixing the drug with a carrier such as waxes, oils, fats, and soluble polymers which are gradually disintegrated by the environment resulting in release of the drug. Much attention has been directed to the reservoir type of device, i.e., a device in which a drug is encased within a polymeric container, with or without a solvent or carrier, which allows passage of drug from the reservoir.
Another type of drug delivery device is the monolithic type in which a drug is dispersed in a polymer and from which the drug is released by degradation of the polymer and/or by passage of the drug through the polymer. Ethylene-vinyl acetate (EVA) copolymer is a well known representative of an imperforate polymer (Rhine, W D, et al, Journal of Pharmaceutical Sciences 69:265-270, 1980; Sefton, M. V., et al, Journal of Pharmaceutical Sciences, 73:1859-1861, 1984; Cohen, J., et al, J. Pharm. Sci., 73:1034-7, 1973). The release kinetics of a drug from a polymeric delivery system are a function of the agent's molecular weight, lipid solubility, and charge as well as the characteristics of the polymer, the percent drug loading, and the characteristics of any matrix coating. The importance of these factors coupled with the specific pharmacology, toxicology, and therapeutic goals necessitate that the design of a polymeric implant for a specific agent must be carefully constructed.
Ku et al, J. Pharm. Sci., 74, p. 926 (1985) describe a multiple-hole approach to obtain zero order release.
The sustained parenteral delivery of opioid antagonists and agonists has been an area of considerable interest because first, it may afford a new approach to the treatment of opioid drug abuse and second, the undertreatment of pain is widely recognized throughout the world.
A. Narcotic Antagonist: Naltrexone
Over the past two decades, a variety of approaches have been attempted using polymers containing narcotic antagonists in an effort to prevent drug abuse. The release characteristics of these antagonists are less critical than those of the pure agonists as evidenced by the first-order kinetics noted in the literature.
1. Glycerine implants
2. Cholesterol-glyceryltriesterate demonstrated first order kinetics in rats
3. Glutamic acid and leucine--biodegradable
4. Polylacticlglycolic acid (PLGA) beads
B. Narcotic Mixed Agonist/Antagonist: Buprenorphine
First order kinetic release using an agent which is not preferred for the treatment of chronic pain.
1. Cholesterol-glyceryltriesterate demonstrated first order kinetics in rats.
C. Narcotic Agonist: Morphine
Morphine is an excellent agent for the treatment of pain but is seven times less potent than hydromorphone and thus, is much less suitable for long-term subcutaneous implant. Many of these implants have demonstrated first-order kinetic release which would threaten the lives of patients receiving implants containing lethal amounts of opioids.
1. Polymeric silicone elastomer
2. Silicone with sodium alginate (swells on contact with water to release drug)
3. Pellets
4. Polyanhydride formulation
D. EVA Implants
EVA (ethylene vinyl acetate) polymers have been used to deliver many classes of drugs: Hormones (i.e., prednisolone, insulin), antineoplastic agents (i.e., 5FU, adriamycin), proteins (i.e., albumin, immunogloblins), neurotransmitters (i.e., dopamine), and antibiotics. A burst of these agents is inconsequential compared to a burst of potent opioids.
1. Prednisolone (Miyazaki, S., et al, Chem. Pharm. Bull (Tokyo), 29:2714-7, 1981
2. 5FU (Wyszynski, R. E., et al, J. Ocul. Pharmacol., 5:141-6, 1989)
3. Adriamycin (Lin, S. Y., et al, Biomat Art Cells Art Org., 17:189-203, 1989.
4. Insulin (Brown, L., et al, Diabetes, 35:692-7, 1986; Brown, L., et al, Diabetes, 35:684-91, 1986)--EVA coated and with hole in one face of the polymer giving near constant release rates.
5. Nerve Growth Factor (Hofman, D., et al, Bxp Neurol, 110:39-44, 1990)
6. Immunoglobulin (Radomsky, M. L., et al, Biomaterials, 11:619-24, 1990)
7. Albumin (Niemi, S. M., et al, Lab Anim. Sci., 35:609-12, 1985)
8. Dopamine/Levodopa (During, M. J., et al, Ann. Neurol., 25:351-356, 1989; Sabel, B. A., et al, Ann. Neurol., 28:714-717, 1990)
Mechanisms for making EVA polymers and tests of their biocompatibility and non-inflammatory nature have been described in the literature. Brown, L. R., et al, J. Pharm. Sci., 72:1181-5, 1983; Langer, R., et al, J. Biomed. Mater. Res., 15:267-77, 1981; and Niemi, S. M., et al, Lab. Anim. Sci., 35:609-12, 1985, all describe the non-inflammatory nature of the polymer and techniques for polymer manufacture.
Critical factors involved in changing the release characteristics of drugs from EVA polymer have been described (Brook, I. M., et al, Br. Den. J., 157:11-15, 1984).
U.S. Pat. No. 5,153,002, hereby incorporated by reference, describes a cube with 5 sides coated with impermeable layer and a cylinder with all but one flat side coated. A hemisphere with impermeable coating (paraffin) except for exposed cavity in the center face provides zero order kinetics for albumin release (Hsieh,. D. S., et al, J. Pharm. Sci., 72:17-22, 1982). EVA with impermeable coating of polymer with hole in the center of one face provides zero order kinetics for insulin release. Drug particle size, drug loading, and matrix coating all significantly affect release kinetics (Rhine, W. D., et al, J. Pharm. Sci., 69:265-70, 1980).
Grossman et al (Proceedings ASCO, Vol. 19, p337 (1991)) describe a delivery system where hydromorphone was embedded into a controlled release matrix made of poly-[ethylene-vinyl acetate].